Many of the investigations in the genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies. The studies of melanoma can be considered a paradigm. Dysplastic nevi were first recognized in the setting of melanoma-prone families. We have recently completed a multi-institution study of the role of dysplastic nevi in consecutive newly diagnosed melanoma patients. Dysplastic nevi appear to be the central risk factor for melanoma, conferring approximately a 10-fold increased risk in those individuals with multiple dysplastic nevi. In addition, an area of controversy has been whether or not the clinical diagnosis of dysplastic nevi is reproducible. Among six experienced clinicians in this study, the clinical diagnosis of dysplastic nevi from photographs was highly reproducible. Increased numbers of small or large common acquired nevi conferred an independent, but much smaller risk (two-to threefold) compared to dysplastic nevi. Other cohorts were also evaluated for the risk of cancer including patients with Beckwith-Wiedemann syndrome, and first and second degree relatives of patients with Ewing's sarcoma. Patients with Beckwith-Wiedemann syndrome were found to have an extremely high risk of Wilms' tumor, hepatoblastoma and neuroblastoma. Those who had hemihypertrophy were at fourfold increased risk of developing Wilms' tumor compared to those without hemihypertrophy. Relatives of patients with Ewing's sarcoma had a two- fold increased risk of melanoma, a threefold increased risk of brain cancer, and a two- fold increased risk of stomach cancer.